Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 24;9(2):510.
doi: 10.3390/cells9020510.

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Maria Letizia Taddei  1 , Laura Pietrovito  2 , Angela Leo  2 , Paola Chiarugi  2   3
Affiliations
Review

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Maria Letizia Taddei et al. Cells. .

Abstract

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

Keywords: acidity; immune response; lactate; microenvironment; sarcoma.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Lactate has a key role in cancer progression. Microenvironmental secreted lactate increases angiogenesis, motility and migration of cancer cells. Lactate is directly involved in the ‘immune escape’ by decreasing activation of T cells and promoting Treg proliferation. Lactate increases extracellular acidosis of the tumor microenvironment (TME) stimulating chemoresistance.
Figure 2
Figure 2
Lactate and the Immune response. Lactate in the tumor microenvironment impairs immune surveillance by blocking natural killer (NK) cells and tumor infiltrating T cells. Lactate-rich milieu promotes Treg cell survival and their immunosuppressive function. Moreover Lactate stimulates the M2 pro-tumoral polarization in macrophages and activates mesenchymal stem cells (MSCs).
Figure 3
Figure 3
Lactate trafficking in tumor and stromal cells. Lactate shuttles through monocarboxylate transporter (MCT) present both in tumor and stromal cells. GPR81, a specific receptor for lactate is expressed on stromal cells and on different cancer cells, mediating chemoresistance, angiogenesis, decreasing lipolysis and up-regulating MCT1 expression.
See this image and copyright information in PMC

References

    1. Trama A., Badalamenti G., Baldi G.G., Brunello A., Caira M., Drove N., Marrari A., Palmerini E., Vincenzi B., Dei Tos A.P., et al. Soft tissue sarcoma in Italy: From epidemiological data to clinical networking to improve patient care and outcomes. Cancer Epidemiol. 2019;59:258–264. doi: 10.1016/j.canep.2019.02.012. - DOI - PubMed
    1. Hui J.Y. Epidemiology and Etiology of Sarcomas. Surg Clin. North Am. 2016;96:901–914. doi: 10.1016/j.suc.2016.05.005. - DOI - PubMed
    1. De Vita A., Mercatali L., Recine F., Pieri F., Riva N., Bongiovanni A., Liverani C., Spadazzi C., Miserocchi G., Amadori D., et al. Current classification, treatment options, and new perspectives in the management of adipocytic sarcomas. Onco. Targets Ther. 2016;9:6233–6246. doi: 10.2147/OTT.S112580. - DOI - PMC - PubMed
    1. Urla C., Warmann S.W., Sparber-Sauer M., Schuck A., Leuschner I., Klingebiel T., Blumenstock G., Seitz G., Koscielniak E., Fuchs J. Treatment and outcome of the patients with rhabdomyosarcoma of the biliary tree: Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS) BMC Cancer. 2019;19:945. doi: 10.1186/s12885-019-6172-5. - DOI - PMC - PubMed
    1. Ehnman M., Larsson O. Microenvironmental Targets in Sarcoma. Front Oncol. 2015;5:248. doi: 10.3389/fonc.2015.00248. - DOI - PMC - PubMed

Publication types